PPARgamma is an orphan nuclear receptor implicated in diabetes, hypercholesterolemia, and breast cancer that has no known antagonist. We are designing, synthesizing, and testing candidate antagonists for PPARgamma based on the chemical structure of known antagonists and agonists. SAR data on these candidates along with sequence homology, evaluated with Computer Graphics Laboratory resources, contributes to our understanding of how small molecule antagonists block activity of nuclear receptors.